Cutaneous mets, can present as single or multiple painless lesions (papules, nodules, ulcer) that are discovered at the same time with the primary tumor, before a diagnosis of internal malignancy or many months/years after.

Some studies say breast mets are most common to the skin, some say lung is most common, followed by head and neck and colorectal cancers. In the collective experience of the participants of #dermpathJC, it’s been breast carcinoma metastases.

Here’s an excellent workup algorithm for epithelioid cutaneous mets to the skin.

– Renal cell carcinomas: typically nonreactive for CK7, CK20 and positive for pancytokeratin AE1/AE3, EMA, CD31, RCC and CD10. RCC mets are also positive for PAX8, however this is also positive in thyroid, Mullerian, and thymic tumors.

– In contrast, pagetoid SCC will be p63 and CK5/6 positive, but mammary and extramammary Paget’s will be p63 negative and CK7+.

– The most useful IHC to differentiate between metastatic breast and primary cutaneous tumors – majority of the participants recommend p63 in conjunction with history and imaging. Sweat gland carcinomas strongly express p63, CK14, CK5, and CK17, however, the latter three immunohistochemical stains are not readily available in all labs.

– GATA3 stains breast carcinomas strongly, but has also been shown to be positive in trichofollicular and sebaceous neoplasms, as well as urothelial carcinoma, parathyroid gland neoplasms, salivary gland neoplasms, and pheochromocytomas.

GYNECOLOGIC:

– Ovarian and endometrial: CK7+ and PAX8+, Endocervix adenocarcinomas: CK7+ and EMA+/-. All three are CK20 negative and show variable ER and PR expression. Endometrioid morphology ddx includes pilomatrical carcinomas, in this instance p63 will be helpful to differentiate primary cutaneous adnexal neoplasm from a metastasis.

MELANOMA:

– Metastases are S100 and SOX10 positive. Melan-A and HMB-45 can be variable.

LYMPHOMA and LEUKEMIA:

– Authors suggest that CD3, CD20, CD30 and muramidase panel is helpful for initial evaluation of atypical lymphoid infiltrates, however majority of the #dermpathJC participants agree that this is a very limited initial panel and should also include: PAX5 always for B-cells and at least 2 markers for each cel lineage.

SARCOMA:

– True metastatic sarcomas to the skin are extremely rare.

– An entity worth noting: epithelioid sarcoma, which has high metastic potential and high mortality. These show positivity for CD34 in up to 50% of cases, as well as CK AE1/3 and EMA. SMARCB1/INI1 22q11 deletion via loss of nuclear INI1 staining.

That’s all folks for now, until next #dermpathJC, stay happy and curious,

This month’s journal club discussed a rare skin neoplasm that closely resembles the solid areas of microcystic adnexal carcinoma (MAC). The article was a good review of the histologic, and immunohistochemical features of this entity.

In case you missed our discussion this week, the summary is provided below:

Only 16 cases of sold carcinoma have been previously published. This paper presents 14 additional cases of sold carcinoma and reviews their morphologic and immunohistochemical features.

Histology:

Groups of neoplastic epithelial cells with small monomorphous nuclei.

Cells form small solid aggregates that vary in size and shape and fill the dermis and extend through adipose tissue.

Nuclear atypia and mitotic figures are rare.

Perineural invasion and infiltrative borders are identified.

Small cornifying cysts/follicular derived cysts can be found in the upper part of the neoplasm.

Some nests show clear cell features without a prominent basal cell layer.

These cells showed abundant cytoplasm, single nucleolus, and their nuclei tended to be located near the apices of the cells

p53 is associated with uncontrolled proliferation and interpreted as an indicator of aggressive behavior and was only expressed in less than 5% of cells in the tested cases.

p63 shows a homogenous expression than in classic MAC.

CK19 is positive in some small ductal structures within the neoplasm

PHLDA-1 was negative in the cases studied (unlike previous papers). It appeared to stain part of the epithelium of cystic structures.

Discussion:

Clinicians must determine whether this is a unique clinicopathologic entity or if it belongs to the spectrum of MAC.

Differential diagnosis includes:

Clear-cell dermal duct tumor

Differentiating features: Absence of cystic structures on the superficial aspect of the neoplasm in dermal duct tumor, and absence of infiltrative pattern without perineural invasion.

Sclerosing basal cell carcinoma

Differentiating features: BerEP4 would be positive in both sclerosing and clear cell BCC and negative in solid carcinoma/solid variant of MAC.

Desmoplastic trichoepithelioma

Tumor cells are basaloid and show presence of rims of collagen bundles around the neoplastic cell cords as well as absence of perineural involvement. Additionally, are confined to the upper/mid dermis.

Solid variant of MAC vs classic MAC:

Classic MAC clinically presents in locations such as lips and face and rarely the scalp. Whereas, the current series, scalp location seems to be more associated with the solid variant of MAC.

Solid carcinoma should be referred to as the solid variant of MAC, histopathologic features of this entity belong to the MAC morphologic spectrum.

This month’s journal club article discussed a topic that gives many of us much consternation, pigmented lesions of the nail unit. The article was a good overall review in many regards; there was discussion (with images) of the clinical features of melanocytic lesions and the concerning signs, as well as a review of the epidemiology, histology, and molecular findings. The learning objectives for the article were very well laid out, and there are accompanying CME questions for obtaining AMA PRA Category 1 credits.

It was a lively discussion, and those active in the discussion overall agreed with the author’s summary and findings.

There were a few take home points from the paper and subsequent discussion, which touched on all aspects:

Embryology:

Proximal nail matrix = predominantly dormant melanocytes

Distal nail matrix = active and dormant melanocytes (more likely for a melanocytic lesion to arise within this zone)

Epidemiology:

Melanocytic macule more common in adults

Nevi more common in children

Clinical:

Longitudinal melanonychia not always due to a melanocytic lesion (Fungus, drugs, trauma, infection, etc can be causative)

Amelanotic subungual melanoma has been reported at rates between 15-50% (while they only comprise 2-8% of melanomas at other sites)

Sampling:

Many seem to groan with nail clippings to evaluate for a melanocytic lesion

If clippings are sent, if negative they will usually be emblazoned with a caveat in an comment

Histology:

Most peoples malignant lesions have been composed of melanoma in situ with invasive melanoma making up the minority.

Immunohistochemistry:

SOX10 not as useful in the nail unit as in other parts of the body

Mart-1 / Melan A are preferred, and felt to work better

Some also order a Fontana Mason in addition

Molecular:

Subungual melanoma more commonly harbor KIT mutations

Predictions through immunohistochemistry has thus failed to be predictive of molecular aberrations

Hair follicle “bulges” (der Wulst) are commonly seen in dermpath sections. How they differentiate from BCC – usually vertically oriented, surrounded by normal dermis, prominent basement membrane, no mitoses, no atypia and lack of myxoid stroma. Normal structure of hair follicles in the central facial skin.

PEH (Pseudoepitheliomatous hyperplasia) can be associated with many different types of lesions. Here is a nice summary table from @SGottesmanMD.

Most dermpathJC participants agree that verrucous carcinoma can be quite impossible to distinguish from pseudoepitheliomatous hyperplasia in certain scenarios. This is where additional clinical information may be helpful.

Pseuodsarcomatous fibroepithelial polyp – fatty core which shows pleomorphic lipoblast-like cells which have similarity to pleomorphic lipomas and some deep soft tissue sarcomas (liposracoma). These changes are thought to be of a degenerative nature. They are very rare as most dermpathJC participants have never seen such changes in fibroepithelial polyps. @JMGardnerMD is wondering if some of these are in the pleomorphic fibroma/lipoma spectrum, and would be cool to do RB1 on a specimen like this. Additional reading about loss of retinblastoma in pleomorphic fibroma: https://www.ncbi.nlm.nih.gov/m/pubmed/28543636/

In contrast, Dr. Singh explained that morpheaform can be less than 5 cells thick. “In short, morpheaform tends to have smaller basaloid nests. But to stress again many consider them as same of overlapping features.”

Others commented that in the morpheaform subtype they also look for dense fibrous/keloid-like collagen fibers

Basosquamous: Zones contain cells with intermediate features between the two. The basaloid component stains positive for BerEP4 and the squamous areas express MUC1 (EMA)

Melanocytic Tumors:

This new approach to melanoma classification was appreciated by many in the Dermpath JC twitter community as there is a higher emphasis on the chronicity of sun damage and how it impacts certain pathways in melanoma progression.

Two main pathways CDKN2A pathway and the MAPK pathway were discussed.

Dysplastic Nevi:

Low Grade: Moderate cytologic and architectural atypia

High Grade: Severe cytologic and architectural atypia

BAPOMA: Combined nevus with a benign nevic component and almost a spitzoid component. Some spitz like areas show multinucleation with an admixed infiltrate.

BAP1 lost especially present in the larger cells. BRAF mutations mostly also seen.

New Entities:

Endocrine mucin producing sweat gland carcinoma

Low-grade neuroendocrine neoplasm

Predilection for eyelid and periorbital skin. However, occurrence in an extrafacial location has also been reported.

Background: Histologic distinction between condyloma acuminatum and various benign and malignant condyloma-like lesions in the anogenital area poses a common diagnostic challenge to pathologists across subspecialties.

Aim of study: To review the overlapping and distinguishing features of condyloma acuminatum and its mimics, and to clarify confusing terminology and diagnostic criteria for problematic entities.

Results: Correct diagnosis of condyloma acuminatum and condyloma-like lesions has important clinical implication and entails familiarization with their clinical presentations and histopathologic features. Contrary to historical belief, giant condyloma acuminatum and verrucous carcinoma should be considered distinct entities based on different pathogenetic pathways. Ancillary tools available for identifying and genotyping human papillomavirus can aid in diagnosis when histopathologic findings are inconclusive. Recognition of relatively rare entities such as bowenoid papulosis, epidermolytic acanthoma, and verruciform xanthoma would avoid overdiagnosis and unnecessary, overaggressive treatment.

Limitations: This was a literature review and did not present original data.

○ Modalities: ISH appears most popular (though some use PCR), sendout labs used included ARUP and Mayo

○ Most do not order HPV testing routinely; will order upon clinician request

○ Important to note that there can be false positives and false negatives; some condy can be caused by high risk or HPV types other than 6/11, so condy that comes back as HPV low risk negative by ISH may be a false negative

● LAST terminology was discussed: many participants incorporate LSIL and HSIL into diagnosis of HPV related lesions of the anogenital region

○ Some only use “condyloma” for papillomatous low grade squamous lesions in the vulva and reserve LSIL for lesions that appear flat, others use both terms (“condyloma (LSIL)”)

○ It was noted that the ISSVD (International Society for the Study of Vulvovaginal Disorders) published terminology in 2015 highlighting specific issues related to vulvar SIL in the LAST criteria; they noted that LSIL should be used in regards to “flat condyloma or HPV effect” and also emphasized that LAST does not refer to differentiated VIN, which is considered a separate, non-HPV related form of high grade VIN (https://www.ncbi.nlm.nih.gov/pubmed/26704327)

● Diagnosis of bowenoid papulosis relies on clinical correlation; suggested approach by some participants would be to diagnose case as HSIL/VIN3 and add comment that it could be c/w bowenoid papulosis in the appropriate clinical setting

● Giant condy vs verrucous CA:

○ traditionally (and still in some texts) taught that both are HPV-related, but while giant condy is usually associated with HPV 6/11, verrucous CA not HPV-related in studies with cases defined by strict histopathologic criteria

The month’s journal club article reviewed the recently published work by the American Society of Dermatopathology on appropriate use. This article is the first of what seems like will be several works from the American Society of Dermatopathology (ASDP) with input from the American Academy of Dermatology (AAD) and the College of American Pathologists (CAP) on appropriate use criteria as it applies to the field of Dermatopathology; specifically the group addressed 211 clinical scenarios and 12 ancillary studies. This publication outlined the appropriateness (without comparison between tests or consideration of costs) of 12 ancillary tests.

The journal club was once again maintained a lively discussion with a good number of participants from all over, with over 30 participants tweeting over 200 times and leaving 762.563K impressions over the following week.

All together the active participants seemed to agree with the sentiments of a comment made by @MightyDermPath that the work was not very controversial, but that it was an important start.

It was a common comment that the article was very table heavy that made for some dense reading. However, the upside being it was very easy to go back and read through their thought process.

The AUC took the above systematic approach to stratifying their recommendations are rarely appropriate, uncertain, and usually appropriate. Raters were also allowed use an “OUT” options if they felt that consultation with the clinician was necessary to determine the appropriateness, and this occurred in only 9 clinical scenarios where >3 panel raters used the OUT option. Altogether they rated 211 clinical scenarios and a consensus was reached for 188 (89%) of them. The major issues to be addressed were separated into general groups: Lymphoproliferative, melanocytic, soft tissue, Muir-Torre syndrome mismatch repair IHC, Other (HPV, ISH, IHC).

Lymphoproliferative group:

B and T cell receptor rearrangement studies were addressed in this group.

Melanocytic group:

The use of FISH, CGH and qRT-PCR were addressed in this group.

Soft tissue group:

FISH testing for EWSR1 for clear cell sarcoma and t(17;22) in DFSP were discussed in this group.

Muir-Torre syndrome mismatch repair IHC:

The use of an IHC antibody panel for screening of Muir-Torre syndrome (a subset of Lynch) were discussed in this group.

Other (HPV, ISH, IHC):

The use of IHC or ISH in the evaluation of HPV association of different squamous lesions was evaluated in this group.

While the article was certainly very chart heavy, it is probably the best way to present the data that the working group found, as they were very thorough in addressing a number of clinical scenarios for each ancillary modality that they addressed. This seems to be not only a very thorough way to address these topics but a very usable way to present the information to those in practice who will be looking for an “at a glance” way to determine test appropriateness.

@JRamirezMD said that the suggestions published were not very different from the way that he currently practices, and others seemed to echo his statements about their own practice habits.

The authors say, and the participants of September 2018 #dermpathJC seemed to agree, this is a good place to start, but that these sorts of guidance works will need to evaluated periodically as technology changes and with the more evidence based support the better. Types of works like these are important for political reasons as well as self policing is an important part of appropriate medical practice in this day and age.